The direct introduction of a biologically active polypeptide into the cells of a patient can have significant therapeutic value. However, this approach also has several drawbacks. Of primary concern is the risk of potential toxicities, particularly at dosages sufficient to produce a biological response to the polypeptide. The clinical impact of a polypeptide is also limited by its relatively short half-life in vivo, which usually results from its degradation by proteases present in the target tissue. Moreover, polypeptides, which are injected into a tissue typically enter the blood circulation before they have a significant therapeutic effect on the tissue into which they were injected.
For these reasons, gene therapy is envisioned as a potentially definitive treatment for a variety of diseases or clinical conditions including cancer, genetic disorders, immune diseases, cardiovascular diseases, viral infections, and in clinical transplantation.
Clinical trials aimed at restoring defective genes are currently proposed for treating cancer. Thus, in lung cancer and in head and neck cancer, for example, clinical trials for restoration of defective p53 have consistently showed evidence of p53 gene transduction and expression, and apoptosis (Moon et al. (2003) Clin. Cancer Res. 9: 5055-5067). Similarly, patients with severe combined immunodeficiency (SCID) treated with adenosine deaminase gene have shown significant immune reconstitution leading to protective immunity (Engel et al. (2003) Curr. Opin. Mol. Ther. 5: 503-507).
Additionally, silencing of undesired genes using antisense oligonucleotides or inhibitory RNA (e.g., siRNA, miRNA, RNAi) directed against these genes also offers much hope for the treatment of a variety of diseases. For example, over expression of many growth factors was found to be correlated with cancer development. Antisense oligonucleotides against such growth factors have been shown to be useful in ameliorating cancer growth (Hirai et al. (2003) J. Gene Med. 5: 951-957).
It is clear, however, that gene therapy can be improved further. Promising avenues include improved gene delivery systems, design of immunogen and anti-angiogenesis gene therapies, design of interfering RNA, and adjuvant use of gene therapy.
U.S. Pat. No. 5,749,847 to Zewert et al. discloses a method for delivering a nucleotide into an organism. The method includes applying a composition containing a nucleotide to epidermis of an organism, and then electroporating the epidermis so as to cause at least a portion of the composition to pass across the epidermis and hence delivering the nucleotide to the organism.
U.S. Pat. No. 6,009,345 to Hofmann provides an apparatus and methods for transdermal delivery of drugs or genes that combine electroporation and iontophoresis. While electroporation forms new pathways through the stratum corneum, iontophoresis provides the driving force necessary to transport the drugs or genes through these pathways into the underlying tissue.
U.S. Pat. No. 6,527,716 to Eppstein discloses a method of delivering a nucleic acid into an organism, which includes ablating a biological membrane by the use of a heat conducting element and thereby porating the membrane in a selected area, applying an electromagnetic field to the selected area, and then contacting the selected area with a nucleic acid under conditions whereby the electromagnetic field actively induces the flux of the nucleic acid into the organism. Thus, ablating and forming micro pores in a biological membrane according to U.S. Pat. No. 6,527,716 involves a heat element that is held in contact with the biological membrane, and as the heat element absorbs energy it causes thermal ablation of the biological membrane, and the nucleic acid is delivered into the organism driven by the electromagnetic field.
There remains an unmet need for efficient apparatus and methods for intradermal or transdermal delivery of polynucleotides, which do not require the provision of a driving force for the delivery of the polynucleotides.